The elongation stage of eukaryotic messenger RNA synthesis is a major site for the regulation of gene expression (Reines, D. et al., Trends. Biochem. Sci. 21:351-355 (1996), Bentley, D. L., Curr. Opin. Genet. Dev. 5:210-216 (1995)). Moreover, a growing body of evidence suggests that mis-regulation of elongation may be a key element in a variety of human diseases (Aso, T. et al., J. Clin. Invest. 97:1561-1569 (1996)).
To date, one virally encoded protein (Tat) and five cellular proteins (SII, P-TEFb, TFIIF, Elongin (SIII), and ELL) have been defined biochemically and shown to be capable of controlling the activity of the RNA polymerase II elongation complex. Among these elongation factors, three have been implicated in human disease. The HIV-1 encoded Tat protein is required for efficient transcription of HIV-1 genes and for productive infection by the virus (Jones, K. A. & Peterlin, B. M., Annu. Rev. Biochem. 63:717-743 (1994)). Elongin (SIII) is a potential target for regulation by the product of the von Hippel-Lindau (VHL) tumor suppressor gene, which is mutated in the majority of clear-cell renal carcinomas and in families with VHL disease, a rare genetic disorder that predisposes individuals to a variety of cancers (Duan, D. R. et al., Science 269:1402-1406 (1995), Kibel, A. et al., Science 269:1444-1446 (1995)). The ELL gene on chromosome 19pl3.1 was originally isolated as a gene that undergoes frequent translocations with the Drosophila trithorax-like MLL gene on chromosome 11q23 in acute myeloid leukemia (Thirman, M. J. et al., Proc. Natl. Acad. Sci. U.S.A. 91:12110-12114 (1994), Mitani, K. et al., Blood 85:2017-2024 (1995)).
This indicates that these proteins have an established, proven history as therapeutic targets. Clearly there is a need for identification and characterization of further related proteins which can play a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, AIDS and neoplastic disorders, among others.